Glioblastomas (GBM) are the most common primary brain tumor and the most lethal. Conventional therapy of surgical resection followed by the combination of radiation and chemotherapy and adjuvant chemotherapy offers only palliation and recurrence is nearly universal. The failure of this approach is due to numerous factors that ultimately promote therapeutic resistance of the tumor. One underlying cause of therapeutic resistance is a subpopulation of cells within GBM called cancer stem-like cells (CSCs) that harbor the more malignant properties of GBM and drive the growth of these tumors. Our overall objective is to elucidate points of fragility for CSCs and develop effective treatment modalities that will inclusively target this tumor-propagating subset of cells. To this end, we have identified a new therapeutic strategy that utilizes the small molecule curaxin-137 which targets a key DNA modification protein (facilitates chromatin transcription, FACT). We previously demonstrated that disruption of FACT function attenuated key CSC characteristics. Our more recent preliminary data demonstrated that disruption of FACT increased the amount of DNA damage in CSCs and reduced cell viability when combined with radiotherapy. We hypothesize that FACT is a key mediator of the CSC phenotype and a viable therapeutic target that will reduce tumor growth when combined with radiotherapy. Based on this background and preliminary data we propose to, 1) investigate if perturbation of FACT activity enhances the efficacy of radiation by direct alteration of the DNA damage response and, 2) test if inhibition of FACT decreases the radioresistance phenotype of CSCs in vivo and if it can enhance to in vivo efficacy of radiotherapy. These studies will investigate a combination therapeutic approach using a clinically relevant inhibitor that alters the ability of CSCs to drive tumorigenesis, ultimately reducing tumor growth, which can be rapidly integrated into GBM therapy. Moreover, successful execution of this scientific endeavor promises to bring important new insights to the overall cancer biology community.